Cousin lab publish new findings in Cell Reports
Congratulations to the Cousin lab on their new study which discovered a new function for an essential molecule for brain communication and offers new hope in improving brain function in individuals with autism and neurodevelopmental disorders.
The study found that brain activity modifies the function of a specific protein called phosphatidylinositol-4 kinase (PI4-kinase). In resting brain cells, this protein acts like a magnet to attract other molecules, and then during activity, it disperses these molecules to do their jobs. This event sustains a process called neurotransmitter release which is the primary mechanism of brain communication. Specifically, PI4-kinase sustains neurotransmitter release during periods of high brain activity by regulating a process called 'bulk endocytosis'.
“We knew from our previous work that PI4-kinase was a protein that gets modified by GSK3. Since we knew that GSK3 was essential for bulk endocytosis, we thought that its modification of PI4-kinase may have an important role in this process too.” said Professor Mike Cousin, Group Leader at the Simons Initiative for the Developing Brain and co-corresponding author on the paper.
In this study, scientists from the Cousin lab carried out experiments to measure bulk endocytosis activity. They added fluorescent molecules (that were designed to specifically report bulk endocytosis) to brain cells grown on glass coverslips during high activity. These brain cells were manipulated to remove the PI4-kinase and then reintroduce different forms of PI4-kinase with specific functions inhibited.
The team found that the addition or removal of a phosphate group from PI4-kinase was the only manipulation which altered bulk endocytosis. This led to the model where in a resting neuron, PI4-kinase has a phosphate group and recruits molecules important for bulk endocytosis. However, during high brain activity, PI4-kinase loses its phosphate group, which results in liberation of those molecules to perform their jobs.
The next steps for the researchers are to address two of the molecules that are liberated on dephosphorylation of PI4 kinase – AGAP2 and CAMKV, since both were shown in the paper to be essential for bulk endocytosis. AGAP2 is a gene disrupted in autism, suggesting another link between bulk endocytosis and this neurodevelopmental condition.
This research was funded by the Wellcome Trust, Epilepsy Research UK and the Biotechnology and Biological Sciences Research Council.